Considerations in reviewing network meta-analyses of heterogeneous clinical trial designs: a methodological review in Crohn's disease and ulcerative colitis.

Background: Network meta-analysis (NMA) is a common approach to synthesizing efficacy and safety data from randomized controlled trials (RCTs). Within the last 5 years, there has been an increase in the number of published NMAs in the clinical literature. One potential risk of this trend is the acceptance of NMA findings with translation into therapeutic decisions for daily clinical practice without first critically assessing the validity of the method's core assumptions, including trial exchangeability and homogeneity. Methods: We use the recent surge in NMAs of advanced therapies for Crohn's disease (CD) and ulcerative colitis (UC) as a case study to illustrate the risks of overly permissive interpretation practices toward NMA methods and findings. We first highlight the potential violations of core NMA assumptions posed by known sources of heterogeneity across trials in CD and UC, and then outline several methodological strategies, ranging from data handling techniques to meta-regression, that can help to address or mitigate these violations. Results: We put forward a checklist for users of NMAs to aid the interpretation of their results in the context of both methods and study inclusion/exclusion. Conclusions: While NMAs offer important insights into the relative treatment effects of different therapies and useful guidance to healthcare decision-makers, it is important that readers and users of NMA publications carefully review and critically evaluate the methods and results to ensure potential biases introduced by cross-trial heterogeneity are sufficiently mitigated and transparently documented, and that the results of any given NMA are interpreted within the context of the wider literature.